This is an R21 application to study a novel approach to suppress IgE-mediated hypersensitivity. While IgE plays a role in certain types of host defense, notably in reactions to multicellular parasites, such as helminth worms, its undesirable side effects in reactions to harmless, but ubiquitous, environmental antigens (Ags) are of greater clinical significance. Therefore, therapies to suppress IgE mediated hypersensitivity responses are being developed. The long-term goal of this proposal is to treat human allergy and asthma with genetic therapies to suppress IgE. [unreadable] The hypothesis of this proposal is that IgE constant region-reactive superantigen ("macroself Ag") can suppress hypersensitivity reactions when expressed in vivo, and that it can function both by sequestering free IgE and by actively tolerizing membrane IgE-expressing B cells. Because free IgE levels are normally very low, it is further hypothesized that one can induce tolerance or suppression of IgE by treatment with macroself Ag even in intact individuals after sensitization, and that this can be done using a gene therapy approach. [unreadable] These hypotheses will be approached through the generation of genes encoding macroself Ags specifically reactive to mouse and human IgE, and testing the ability of these genes to suppress IgE responses either when expressed as germline transgenes or in a gene therapy setting. Testing the function of human IgE-reactive macroself Ag will be performed in mice engineered to carry human antibody gene loci. Furthermore, IgE macroself Ag-mediated suppression by gene transfer will be assessed both during and after antigenic sensitization. [unreadable] [unreadable]